Iconeus Functional Ultrasound (fUS) preclinical imaging systems
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Neuropharmacology

Neuropharmacology

In a similar way to fMRI, functional ultrasound can be used in neuropharmacology studies to determine time- and dose-dependent effects of drugs on the brain. But unlike fMRI, this ‘pharmaco-fUS’ approach is more sensitive, faster, more reproducible, and compatible with awake animals (eliminating the bias of anesthesia).

Investigating the effect of drugs on functional connectivity

In this study, it was shown that scopolamine (used preclinically as a model for Alzheimer’s disease) leads to rapid and lasting changes in functional connectivity between the two hemispheres of the hippocampus and the neighboring areas of the cortex.

neuropharmacology
In this set of seed-based correlation plots, averaged over five mice, a small area of the hippocampus was used as a ‘seed’, and fUS used to reveal correlations during each of seven motion-free time periods (T1–T7). The initial baseline analyses reveal, as expected, a strong inter-hemispheric correlation within the hippocampus. After scopolamine injection, this connection is stronger and more diffuse, with correlations also shown to neighboring cortical areas. Reproduced from Rabut et al., NeuroImage, 2020 (licensed under CC BY 4.0)

Investigating the effect of drugs on changes in cerebral blood volume

Two recent studies, both from the pharmaceutical company Theranexus, have demonstrated how fUS can be used to investigate the hemodynamic response of the brain to drugs. 

The first of these (shown in the figure) found a synergistic brain response between an AChE inhibitor (donepezil) used to alleviate cognitive symptoms in Alzheimer’s disease and a new drug (mefloquine) targeting connexins. Importantly, this fUS study also complements previous work that showed how the drug combination could reverse scopolamine-induced memory loss, by providing detail on the areas affected.

In the second study (Vidal et al., Neuropharmacology, 2020), the effect of atomoxetine (a potent norepinephrine reuptake inhibitor and treatment for ADHD) was investigated in anesthetized rats. A dose-dependent variation of CBV with time was observed, particularly in brain regions involved in vision.
This study, carried out in mice, shows that although administration of donepezil (DPZ) or mefloquine (MEF) on their own had only limited effects on the blood volume in the hippocampus compared to the baseline, combining them produced a marked reduction (blue line). Reproduced from Vidal et al., Frontiers in Neuroscience, 2020 (CC BY 4.0)
This study, carried out in mice, shows that although administration of donepezil (DPZ) or mefloquine (MEF) on their own had only limited effects on the blood volume in the hippocampus compared to the baseline, combining them produced a marked reduction (blue line). Reproduced from Vidal et al., Frontiers in Neuroscience, 2020 (licensed by CC BY 4.0)

For more on the potential of fUS in this field, take a look at our webinar “Functional ultrasound imaging in pain and pharmacology research”, presented by Dr Sophie Pezet and Dr Benjamin Vidal (authors of the above-mentioned papers).

Establishing PK/PD parameters

Centrally-acting drugs, by directly modulating neuronal activity, can cause changes in blood volume in brain areas where their target receptors are expressed. fUS is therefore an ideal approach for identifying the central mechanism of action of CNS drug leads. Using fUS, you can study the regional selectivity of non-vasoactive drugs and establish essential Pharmacokinetic/Pharmacodynamic (PK/PD) parameters, such as dose–response relationships, in a non-invasive manner.
The effect of a centrally-acting compound in an anesthetized rat, showing how the change in CBV is restricted to the cortex (pale blue). The 3D Allen Mouse Brain Atlas integrated into Iconeus One enables the regions of interest to be reliably defined.

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